Background-Platelets participate in events that immediately precede acute myocardial infarction. Because platelets lack nuclear DNA but retain megakaryocyte-derived mRNAs, the platelet transcriptome provides a novel window on gene expression preceding acute coronary events. Methods and Results-We profiled platelet mRNA from patients with acute ST-segment-elevation myocardial infarction (STEMI, nϭ16) or stable coronary artery disease (nϭ44). The platelet transcriptomes were analyzed and single-gene models constructed to identify candidate genes with differential expression. We validated 1 candidate gene product by performing a prospective, nested case-control study (nϭ255 case-control pairs) among apparently healthy women to assess the risk of future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) associated with baseline plasma levels of the candidate protein. Platelets isolated from STEMI and coronary artery disease patients contained 54 differentially expressed transcripts. The strongest discriminators of STEMI in the microarrays were CD69 (odds ratio 6.2, PϽ0.001) and myeloid-related protein-14 (MRP-14; odds ratio 3.3, Pϭ0.002). Plasma levels of MRP-8/14 heterodimer were higher in STEMI patients (17.0 versus 8.0 g/mL, PϽ0.001). In the validation study, the risk of a first cardiovascular event increased with each increasing quartile of MRP-8/14 (P trend Ͻ0.001) such that women with the highest levels had a 3.8-fold increase in risk of any vascular event (PϽ0.001).Risks were independent of standard risk factors and C-reactive protein. Conclusions-The
Background— Myeloid-related protein (MRP)-8 (S100A8) and MRP-14 (S100A9) are members of the S100 family of calcium-modulated proteins that regulate myeloid cell function and control inflammation, in part, through activation of Toll-like receptor-4 and the receptor for advanced glycation end products. A transcriptional profiling approach in patients with acute coronary syndromes identified MRP-14 as a novel predictor of myocardial infarction. Further studies demonstrated that elevated plasma levels of MRP-8/14 heterodimer predict increased risk of first and recurrent cardiovascular events. Beyond its serving as a risk marker, whether MRP-8/14 participates directly in vascular inflammation and disease remains unclear. Methods and Results— We evaluated vascular inflammation in wild-type and MRP-14 –deficient ( MRP-14 −/− ) mice that lack MRP-8/14 complexes with experimental arterial injury, vasculitis, or atherosclerosis. After femoral artery wire injury, MRP-14 −/− mice had significant reductions in leukocyte accumulation, cellular proliferation, and neointimal formation compared with wild-type mice. In a cytokine-induced local Shwartzman-like reaction that produces thrombohemorrhagic vasculitis, MRP-14 −/− mice had significant reductions in neutrophil accumulation, lesion severity, and hemorrhagic area. In response to high-fat feeding, mice doubly deficient in apolipoprotein E and MRP-8/14 complexes had attenuation in atherosclerotic lesion area and in macrophage accumulation in plaques compared with mice deficient in apolipoprotein E alone. Conclusion— This study demonstrates that MRP-8/14 broadly regulates vascular inflammation and contributes to the biological response to vascular injury by promoting leukocyte recruitment.
This study demonstrates that GP Ibalpha is a physiologically relevant ligand for alphaMbeta2 and that integrin engagement of GP Ibalpha is critical to leukocyte function and the biological response to vascular injury. These observations establish a molecular target for selectively disrupting leukocyte-platelet complexes that promote inflammation in thrombosis and restenosis.
Expression of the gene encoding the S100 calcium-modulated protein family member MRP-14 (also known as S100A9) is elevated in platelets from patients presenting with acute myocardial infarction (MI) compared with those from patients with stable coronary artery disease; however, a causal role for MRP-14 in acute coronary syndromes has not been established. Here, using multiple models of vascular injury, we found that time to arterial thrombotic occlusion was markedly prolonged in Mrp14 -/-mice. We observed that MRP-14 and MRP-8/ MRP-14 heterodimers (S100A8/A9) are expressed in and secreted by platelets from WT mice and that thrombus formation was reduced in whole blood from Mrp14 -/-mice. Infusion of WT platelets, purified MRP-14, or purified MRP-8/MRP-14 heterodimers into Mrp14 -/-mice decreased the time to carotid artery occlusion after injury, indicating that platelet-derived MRP-14 directly regulates thrombosis. In contrast, infusion of purified MRP-14 into mice deficient for both MRP-14 and CD36 failed to reduce carotid occlusion times, indicating that CD36 is required for MRP-14-dependent thrombosis. Our data identify a molecular pathway of thrombosis that involves platelet MRP-14 and CD36 and suggest that targeting MRP-14 has potential for treating atherothrombotic disorders, including MI and stroke.
Inflammation and thrombosis occur together in many diseases. The leukocyte integrin Mac-1 (also known as integrin αMβ2, or CD11b/CD18) is crucial for leukocyte recruitment to the endothelium, and Mac-1 engagement of platelet GPIbα is required for injury responses in diverse disease models. However, the role of Mac-1 in thrombosis is undefined. Here we report that mice with Mac-1 deficiency (Mac-1−/−) or mutation of the Mac-1-binding site for GPIbα have delayed thrombosis after carotid artery and cremaster microvascular injury without affecting parameters of haemostasis. Adoptive wild-type leukocyte transfer rescues the thrombosis defect in Mac-1−/− mice, and Mac-1-dependent regulation of the transcription factor Foxp1 contributes to thrombosis as evidenced by delayed thrombosis in mice with monocyte-/macrophage-specific overexpression of Foxp1. Antibody and small-molecule targeting of Mac-1:GPIbα inhibits thrombosis. Our data identify a new pathway of thrombosis involving leukocyte Mac-1 and platelet GPIbα, and suggest that targeting this interaction has anti-thrombotic therapeutic potential with reduced bleeding risk.
A critical aspect of mammalian development involves the actions of dedicated repressors/corepressors to prevent unregulated gene activation programs that would initiate specific cell determination events. While the role of NCoR/SMRT corepressors in nuclear receptor actions is well documented, we here report that a previously unrecognized functional interaction between SMRT and a forkhead protein, FOXP1, is required for cardiac growth and regulation of macrophage differentiation. Our studies demonstrate that SMRT and FOXP1 define a functional biological unit required to orchestrate specific programs critical for mammalian organogenesis, linking developmental roles of FOX to a specific corepressor.Supplemental material is available at http://www.genesdev.org.Received November 27, 2007; revised version accepted January 18, 2008. Although activation of transcription has long been recognized as an essential component of gene regulation during development, the critical role of transcriptional repression programs is apparent from the pluripotent stem cell to terminal differentiation events. Nuclear receptors, including retinoic acid and thyroid hormone receptors (RAR and T 3 R), regulate development through both ligand-dependent activation and active repression by unliganded nuclear receptors (Glass and Rosenfeld 2000), and their ability to actively repress transcription in the absence of their cognate ligands is conferred by their interaction with SMRT or with the highly related corepressor NCoR (Chen and Evans 1995;Horlein et al. 1995). NCoR and SMRT also confer transcriptional repression to many additional members of the nuclear receptor superfamily, as well as on a variety of unrelated transcription factors, at least in part due to corecruitment of histone deacetylase proteins (HDACs) (Privalsky 2001;Jepsen and Rosenfeld 2002;Jones and Shi 2003).The forkhead family of transcription factors, which includes over a hundred genes in several species named for the forkhead-box (FOX) DNA-binding domain, has been characterized as both transcriptional activators and repressors (for review, see Wijchers et al. 2006). While all four FoxP family members function as transcriptional repressors, the mechanism of this repression remains largely uncharacterized, although FoxP3 has been shown to be capable of interacting with HDAC proteins (Li et al. 2007). Gene deletion studies have revealed that FOXP1 mutant mice have defects in cardiac morphogenesis, a thin ventricular myocardial compact zone, and lack of proper ventricular septation, which together result in embryonic death at embryonic day 14.5 (E14.5) (Wang et al. 2004). Interestingly, maintaining the proper balance of histone acetylation/deacetylation is critical for proper cardiac development and growth (Backs and Olson 2006;Montgomery et al. 2007), leading us to consider potential links between FOXP1 and recruitment of specific corepressor complexes.Here we report that deletion of the gene encoding the corepressor SMRT resulted in specific developmental abnormalities in...
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